Elsevier

Neurobiology of Disease

Volume 25, Issue 1, January 2007, Pages 92-104
Neurobiology of Disease

Interleukin-1β mediates GDNF up-regulation upon dopaminergic injury in ventral midbrain cell cultures

https://doi.org/10.1016/j.nbd.2006.08.019Get rights and content

Abstract

We recently proposed the involvement of diffusible modulators in signalling astrocytes to increase glial cell line-derived neurotrophic factor (GDNF) expression after selective dopaminergic injury by H2O2 or l-DOPA. Here we report that interleukin-1β (IL-1β) is involved in this crosstalk between injured neurons and astrocytes. IL-1β was detected only in the media from challenged neuron–glia cultures. Exogenous IL-1β did not change GDNF protein levels in astrocyte cultures, and diminished GDNF levels in neuron–glia cultures. This decrease was not due to cell loss, as assessed by the MTT assay and immunocytochemistry. Neither H2O2 nor l-DOPA induced microglia proliferation or appeared to change its activation state. The IL-1 receptor antagonist (IL-1ra) prevented GDNF up-regulation in challenged cultures, showing that IL-1β is involved in the signalling between injured neurons and astrocytes. Since IL-1ra decreased the number of dopaminergic neurons in H2O2-treated cultures, we propose that IL-1 has a neuroprotective role in this system involving GDNF up-regulation.

Introduction

Parkinson’s disease (PD) patients experience motor impairment due to the selective loss of dopaminergic neurons from the substantia nigra pars compacta and consequent dopamine depletion in the caudate-putamen. In addition to dopaminergic cell loss, there is also a significant glial reaction composed mainly of activated microglial cells and, to a lesser extend, of reactive astrocytes (Teismann et al., 2003). A marked increase in the level of pro-inflammatory cytokines in the brain and cerebrospinal fluid of PD patients is also well documented (reviewed by Nagatsu et al., 2000).

Cytokines are important intercellular messengers involved in neuron–glia interactions and in the crosstalk between injury-activated astrocytes and microglial cells, modulating the glial response to injury. Interleukin-1 (IL-1) is often considered the prototypic pro-inflammatory cytokine (Rothwell and Luheshi, 2000). Whereas barely detectable in healthy brain (Vitkovic et al., 2000), IL-1β levels are increased in the brain of PD patients (Mogi et al., 1994), and it has been proposed that the increased levels of IL-1 may contribute to the pathophysiology of PD (Nagatsu and Sawada, 2005). In the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) animal model of PD, IL-1 levels were also found to be increased (Ho and Blum, 1998, Mogi et al., 1998, Grunblatt et al., 2001, Mandel et al., 2002, Ciesielska et al., 2003). Although historically IL-1 has been associated with a pro-inflammatory role, several studies have highlighted the role of IL-1 in the regeneration of the central nervous system. IL-1 was implicated in the induction of different neurotrophic factors after injury, including nerve growth factor (DeKosky et al., 1996), ciliary neurotrophic factor (Herx et al., 2000), and insulin-like growth factor-1 (Mason et al., 2001). Taken together, these data support a role for IL-1 in encouraging repair. In fact, pro-inflammatory cytokines could play a neuroprotective role in PD. For instance, striatal application of IL-1-releasing pellets after 6-hydroxydopamine (6-OHDA)-induced lesion in rats increased the spontaneous recovery of striatal dopaminergic innervation (Wang et al., 1994). Other studies showed a positive correlation between striatal IL-1α levels and dopaminergic reinnervation after MPTP (Ho and Blum, 1998, Hebert et al., 2003). Using knockout mice, IL-1 and IL-6 have also been shown to be involved in dopaminergic sprouting after neurotoxin-induced denervation (Bolin et al., 2002, Parish et al., 2002). Furthermore, intranigral infusion of IL-1β was shown to activate astrocytes and significantly protected nigral dopaminergic cell bodies from a subsequent 6-OHDA lesion (Saura et al., 2003).

Glial cell line-derived neurotrophic factor (GDNF) is a potent factor for the protection of nigral dopaminergic neurons against toxin-induced degeneration in animal models of PD and promotes recovery from motor deficits (Gash et al., 1996, Kordower et al., 2000, Grondin et al., 2002, Dowd et al., 2005). Therefore, GDNF represents a potential therapeutic tool for PD, and some clinical trials have confirmed the efficacy of GDNF in patients with PD (Gill et al., 2003, Patel et al., 2005). In previous studies we demonstrated that H2O2 and l-DOPA increased GDNF protein levels in a concentration- and time-dependent mode in neuron–glia cultures but not in astrocyte cultures. Since conditioned media from H2O2- or l-DOPA-treated neuron–glia cultures increased GDNF mRNA and protein levels in astrocyte cultures, we proposed that diffusible modulators, likely released by damaged neurons, signal astrocytes to increase GDNF expression (Saavedra et al., 2006). To understand the mechanisms involved in neurotrophic factor up-regulation after injury, it is important to identify the molecular mediators involved in their production. In this work, we show that IL-1β is involved in GDNF up-regulation after dopaminergic injury.

Section snippets

Cell culture

Animals were handled in accordance with the national ethical requirements for animal research and with the European Convention for the Protection of Vertebrate Animals Used for Experimental and Other Scientific Purposes. Cells cultures were prepared as previously described (Saavedra et al., 2005, Saavedra et al., 2006). Briefly, postnatal day 1–3 Wistar rat pups were used to prepare ventral midbrain astrocyte cultures, and 75,000 cells were plated onto poly-d-lysine and laminin-coated

H2O2 and l-DOPA increased extracellular levels of IL-1β in neuron–glia but not in astrocyte cultures

We have previously shown that H2O2 and l-DOPA induce dopaminergic cell loss in neuron–glia cultures (Saavedra et al., 2006). Since up-regulation of IL-1β expression has been shown to occur following several types of injury, we investigated the effect of H2O2 and l-DOPA on IL-1β levels in the culture media from ventral midbrain astrocyte or neuron–glia cultures. IL-1β levels were under the detection limit in samples from astrocyte cultures, both in control and challenged cultures. In neuron–glia

Discussion

In previous studies, we showed that the selective injury to dopaminergic neurons with H2O2 or l-DOPA increased GDNF expression in neuron–glia cultures, but not in astrocyte cultures. Since the conditioned media from challenged neuron–glia cultures increased GDNF in astrocyte cultures, we proposed the involvement of diffusible modulators in signalling astrocytes to increase GDNF expression (Saavedra et al., 2006). Here we show that IL-1β is involved in GDNF up-regulation in response to H2O2 or l

Acknowledgments

We are grateful to Dr. Célia Aveleira (Center of Ophtalmology of Coimbra, IBILI, Faculty of Medicine, University of Coimbra, Portugal) for providing the IL-1β and the IL-1RI antibodies and to Dr. Paulo Santos (Center for Histocompatibility, Coimbra, Portugal) for his help with the real-time PCR experiments. This work was supported by the Bissaya Barreto Foundation and the Foundation for Science and Technology, Portugal (Grant SFRH/BD/5337/2001 to Ana Saavedra).

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